Medical aerosol formulation

ABSTRACT

This invention relates to a medicinal aerosol formulation and, more particularly, to a medicinal aerosol formulation an insulin combination and a fluid carrier.

This application claims priority from U.S. provisional applicationSerial No. 60/177,937 filed Jan. 25, 2000, which is incorporated hereinby reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a medicinal aerosol formulation for treatingdiabetes, and more particularly, to a medicinal aerosol formulationcomprising a mixture of an insulin or an insulin analog and anotherβ-cell hypoglycemic medicament.

2. Description of the Related Art

Delivery of drugs to the lung by way of inhalation is an important meansof treating a variety of conditions, including such common localconditions as cystic fibrosis, pneumonia, bronchial asthma and chronicobstructive pulmonary disease and some systemic conditions, includinghormone replacement, pain management, immune deficiency, erythropoiesis,diabetes, etc. Steroids, β2 agonists, anti-cholinergic agents, proteinsand polypeptides are among the drugs that are administered to the lungfor such purposes. Such drugs are commonly administered to the lung inthe form of an aerosol of particles of respirable size (less than about10 μm in diameter). The aerosol formulation can be presented as a liquidor a dry powder. In order to assure proper particle size in a liquidaerosol, particles can be prepared in respirable size and thenincorporated into a colloidal dispersion either containing a propellantas a pressurized metered dose inhaler (PMDI) or air, such as in the caseof a dry powder inhaler (DPI). Alternatively, formulations can beprepared in solution or emulsion form in order to avoid the concern forproper particle size in the formulation. Solution formulations mustnevertheless be dispensed in a manner that produces particles ordroplets of respirable size.

For MDI application, once prepared, an aerosol formulation is filledinto an aerosol canister equipped with a metered dose valve. In thehands of the patient the formulation is dispensed via an actuatoradapted to direct the dose from the valve to the patient.

What is needed and desired is a stable aerosol formulation for thetreatment of diabetes and the conditions related thereto.

SUMMARY OF THE INVENTION

It has surprisingly been found that a novel and stable medicinal aerosolformulation of an insulin or an insulin analog combined with a β-cellhypoglycemic medicament can be obtained without the use of a surfactant,such as sorbitan trioleate. The selected insulin or insulin analog iscombined with another β-cell hypoglycemic medicament, and optionallyother diabetic medicaments such as for example the α cell hormone,glucagon.

DETAILED DESCRIPTION OF THE INVENTION

This application makes reference to U.S. application Ser. No. 09/209,228filed Dec. 10, 1998, now U.S. Pat. No. 6,261,539 B1, issued Jul. 17,2001 which is incorporated hereinto by reference in its entirety.

This invention involves a stable aerosol suspension formulation suitablefor pressurized delivery which comprises (a) a particulate insulincombination, and (b) a suitable fluid carrier.

By an “insulin combination” is meant a selected insulin or insulinanalog combined with at least one other β-cell hypoglycemic medicamentor drug, such as an amylin.

The term “insulin” shall be interpreted to encompass natural extractedhuman insulin, recombinantly produced human insulin, insulin extractedfrom bovine and/or porcine sources, recombinantly produced porcine andbovine insulin and mixtures of any of these insulin products. The termis intended to encompass the polypeptide normally used in the treatmentof diabetics in a substantially purified form but encompasses the use ofthe term in its commercially available pharmaceutical form, whichincludes additional excipients. The insulin ispreferably recombinantlyproduced and may be dehydrated (completely dried) or in solution.

The terms “insulin analog,” “monomeric insulin” and the like are usedinterchangeably herein and are intended to encompass any form of“insulin” as defined above wherein one or more of the amino acids withinthe polypeptide chain has been replaced with an alternative amino acidand/or wherein one or more of the amino acids has been deleted orwherein one or more additional amino acids has been added to thepolypeptide chain or amino acid sequences which act as insulin indecreasing blood glucose levels. In general, the “insulin analogs” ofthe present invention include “insulin lispro analogs,” as disclosed inU.S. Pat. No. 5,547,929, incorporated hereinto in its entirety byreference, insulin analogs including LysPro insulin and humalog insulin,and other “super insulin analogs”, wherein the ability of the insulinanalog to affect serum glucose levels is substantially enhanced ascompared with conventional insulin as well as hepatoselective insulinanalogs which are more active in the liver than in adipose tissue.Preferred analogs are monomeric insulin analogs, which are insulin-likecompounds used for the same general purpose as insulin such as insulinlispro i.e., compounds which are administered to reduce blood glucoselevels.

A suitable β-cell hypoglycemic medicament is one selected from anamylin. An “amylin” includes natural human amylin, bovine, porcine, rat,rabbit amylin, as well as synthetic, semi-synthetic or recombinantamylin or amylin analogs including pramlintide and other amylin agonistsas disclosed in U.S. Pat. No. 5,686,411, and U.S. Pat. No. 5,854,215,both of which are incorporated hereinto by reference in their entirety.

Combined with the insulin combination, e.g. an insulin plus an amylin,is another diabetic medicament. Typically this other medicament is the acell hormone glucagon. Other diabetic medicaments which can be employedare acetohexamide, chlorpropamide, tolazemide, tolbutamide, glipizide,glyburide, glucophage, phentolamine, etc.

For purposes of the formulations of this invention, which are intendedfor inhalation into the lungs, the insulin combination is preferablymicronized whereby a therapeutically effective amount or fraction (e.g.ninety percent or more) of the insulin combination is particulate.Typically, the particles have a diameter of less than about 10 microns,and preferably less than about 5 microns, in order that the particlescan be inhaled into the respiratory tract and/or lungs.

The particulate insulin combination is present in the inventiveformulations in a therapeutically effective amount, that is, an amountsuch that the drug can be administered as a dispersion, an aerosol, suchas topically, or via oral or nasal inhalation, and cause its desiredatherapeutic effect, typically preferred with one dose, or throughseveral doses. The particulate insulin combination is administered as anaerosol from a conventional valve, e.g., a metered dose valve, throughan aerosol adapter also known as an actuator.

The term “amount” as used herein refers to quantity or to concentrationas appropriate to the context. The amount of the insulin combination orformulation that constitutes a therapeutically effective amount variesaccording to factors such as the potency of the particular insulin orinsulin analog and the particular β-cell hypoglycemic medicament ormedicaments used, as well as the other diabetic medicaments, if used,the route of administration of the formulation, and the mechanicalsystem used to administer the formulation. A therapeutically effectiveamount of the insulin combination can be selected by those of ordinaryskill in the art with due consideration of such factors. Generally atherapeutically effective amount will be from about 0.001 parts byweight to about 5 parts by weight based on 100 parts by weight of thepropellant.

Typically, the insulin combination comprises a selected insulin presentin an amount of 0.0001 to about 5 parts by weight of the insulin orinsulin analog to about 0.0001 to about 5 parts by weight of theselected β-cell hypoglycemic amylin or mixture thereof e.g. anamylin/insulin mixture. Typically, the mixtures of β-cell hypoglycemicmedicaments in their respective ranges could be combined with a glucagonor glucagon analog or other diabetic medicament in a concentration rangeof about 0.001 to about 10 parts by weight based on 100 parts by weightof the propellant.

A suitable fluid carrier is selected. A suitable fluid includes air, ahydrocarbon, such as n-butane, propane, isopentane, etc., or apropellant. A suitable propellant is any fluorocarbon, e.g. a 1-6hydrogen containing flurocarbon, such as CHF₂CHF₂, CF₃CH₂F, CH₂F₂CH₃ andCF₃CHFCF₃; a perfluorocarbon, e.g. a 1-4 carbon perfluorocarbon, such asCF₃CF₃, CF₃CF₂CF₃; or any mixture of the foregoing, having a sufficientvapor pressure to render them effective as propellants. Some typicalsuitable propellants include conventional chlorofluorocarbon (CFC)propellants such as mixtures of propellants 11, 12 and 114 or a mixtureof any of the foregoing propellants. Non-CFC propellants such as1,1,1,2-tetrafluoroethane (Propellant 134a),1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixture thereof arepreferred. The propellant is preferably present in an amount sufficientto propel a plurality of the selected doses of drug from an aerosolcanister.

Optionally, a suitable stabilizer is selected. A suitable stabilizer isa “water addition”. As used herein a “water addition” is an amount ofwater which (1) is added, either initially with other components of theaerosol formulation, e.g. insulin combination and propellant, or afterthe other components, e.g. insulin combination, fluid carrier, arecombined and processed, (2) is in addition to the water which is alwayspresent and which develops during processing and/or storage of theaerosol formulation, i.e. “developed” or “nascent” formulation water,and (3) is present in an amount which further stabilizes medicinalaerosol formulation having nascent formulation water.

An aerosol formulation preferably comprises the water addition in anamount effective to more effectively stabilize the formulation relativeto an identical formulation not containing the water addition, i.e.containing only nascent formulation water, such that the insulincombination does not settle, cream or flocculate after agitation soquickly as to prevent reproducible dosing of the insulin combination.Reproducible dosing can be achieved if the formulation retains asubstantially uniform drug concentration for about fifteen seconds tofive minutes agitation.

The particular amount of the water addition that constitutes aneffective amount is dependent upon the particular propellant and on theparticular insulin combination used in the formulation. It is thereforenot practical to enumerate specific effective amounts for use withspecific formulations of the invention, but such amounts can readily bedetermined by those skilled in the art with due consideration of thefactors set forth above. Generally, however, the water addition must bepresent in a formulation in an amount in excess of the concentration ofthe nascent formulation water. Such concentration of nascent formulationwater typically ranges up to 300 parts by weight per one million partsby weight of the total weight of the aerosol formulation. Accordingly,the water addition in excess of this nascent water concentrationtypically ranges from about 10 parts by weight to about 5000 parts byweight per one million parts by weight of the total aerosol formulationweight. Most preferred is that the concentration of the water additionis from about 500 parts by weight to about 5000 parts by weight per onemillion parts by weight of the total weight of the medicinal aerosolformulation.

It is to be emphasized that this is an amount which exceeds the amountof nascent or developed formulation water. It is also to be stressedthat this amount of water addition can be added and initially combinedwith the other components of the formulation, e.g. an insulin and anamylin and fluid carrier, e.g. 1,1,1,2-tetrahydrofluoroethane, or addedto the resultant formulation after these other components have beenprocessed, e.g. prior to or subsequent to storage.

It has surprisingly been found that the formulation of the invention isstable without the necessity of employing a cosolvent, such as ethanol,or surfactants. However, further components, such as conventionallubricants or surfactants, cosolvents, ethanol, etc., can also bepresent in an aerosol formulation of the invention in suitable amountsreadily determined by those skilled in the art. In this regard,reference is made to U.S. Pat. No. 5,225,183, which is incorporated byreference hereinto in its entirety. Typically, a co-solvent such asethanol is added in an amount ranging from 0.5 to 10% by weight of thetotal weight of the formulation.

A most preferred formulation comprises the insulin combination, thefluid carrier, the ethanol cosolvent and the water addition, forexample, an insulin and an amylin medicament, 1,1,1,2-tetrafluoroethane,ethanol and the water addition.

Generally the formulations of the invention can be prepared by combining(i) the selected insulin combination in an amount sufficient to providea plurality of therapeutically effective doses; (ii) the fluid orpropellant in an amount sufficient to propel a plurality of doses e.g.from an aerosol canister; and (iii) optionally, the water addition in anamount effective to further stabilize each of the formulations; and (iv)any further optional components, e.g. ethanol as a cosolvent otherdiabetic medicaments, e.g. glucagon; and dispersing the components. Thecomponents can be dispersed using a conventional mixer or homogenizer,by shaking, or by ultrasonic energy as well as by the use of a beadmillor a microfluidizer. Bulk formulations can be transferred to smallerindividual aerosol vials by using valve to valve transfer methods,pressure filling or by using conventional cold-fill methods. It is notrequired that a component used in a suspension aerosol formulation besoluble in the fluid carrier, e.g. the propellant. Those that are notsufficiently soluble can be coated onto the drug particles in anappropriate amount and the coated particles can then be incorporated ina formulation as described above.

Aerosol canisters equipped with conventional valves, preferably metereddose valves, can be used to deliver the formulations of the invention.It has been found, however, that selection of appropriate valveassemblies for use with aerosol formulations is dependent upon theparticular component and other adjuvants used (if any), on the fluid orpropellant, and on the particular insulin combination being used.Conventional neoprene and buna valve rubbers used in metered dose valvesfor delivering conventional CFC formulations often have less thanoptimal valve delivery characteristics and ease of operation when usedwith formulations containing HFC-134a or HFC-227. Therefore certainformulations of the invention are preferably dispensed via a valveassembly wherein the diaphragm is made of a nitrile rubber such asDB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDMrubber such as Vistalon™ (Exxon), Royalene™ (UniRoyal), BunaEP (Bayer).Also suitable are diaphragms fashioned by extrusion, injection moldingor compression molding from a thermoplastic elastomeric material such asFLEXOMER™ GERS 1085 NT polyolefin (Union Carbide).

Conventional aerosol canisters, coated or uncoated, anodized orunanodized, e.g., those of aluminum, glass, stainless steel,polyethylene terephthalate, and coated canisters or cans with epon,epoxy, etc., can be used to contain a formulation of the invention.

The formulation of the invention can be delivered to the respiratorytract and/or lung by oral inhalation in order to treat diabetes or acondition related to diabetes, which are susceptible of treatment byinhalation. The formulations of the invention can also be delivered bynasal inhalation in order to treat, e.g., diabetes (systemic), or theycan be delivered via oral (e.g., buccal) administration in order totreat, e.g., diabetes.

We claim:
 1. A liquid medicinal aerosol suspension formulation whichcomprises: (a) a therapeutically effective amount of an insulincombination which is an insulin analog combined with at least one otherβ-cell hypoglycemic medicament; and (b) a fluid propellant carrier. 2.The formulation as defined in claim 1 which further includes acosolvent.
 3. The formulation as defined in claim 2 where said cosolventcomprises ethanol.
 4. A liquid medicinal aerosol suspension formulation,which consists essentially of: (a) a therapeutically effective amount ofan insulin combination which is a selected insulin or insulin analogcombined with at least one other β-cell hypoglycemic medicament; and (b)a fluid propellant carrier.
 5. The formulation as defined in claim 4,wherein said insulin combination comprises an insulin which is selectedfrom the group consisting of natural, synthetic, recombinant insulinsand a mixture of the foregoing insulins.
 6. The formulation of asdefined in claim 5, wherein said insulin combination comprises aninsulin analog selected from the group consisting of proinsulin, aninsulin lispro analog, humalog insulin, a super insulin analog or amixture of the foregoing insulins.
 7. The formulation as defined inclaim 5 wherein said insulin combination comprises an amylin and aninsulin selected from the group consisting of lisproinsulin, humaloginsulin, hepatoselective insulin, a recombinant insulin, natural insulinor a mixture of any of the foregoing insulins.
 8. The formulation asdefined in claim 4 or claim 1 wherein said insulin combination comprisesan amylin medicament.
 9. The formulation as defined in claim 4 or 1claim wherein said fluid is selected from the group of propellantsconsisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane or a mixture thereof.
 10. Theformulation as defined in claim 4 or claim 1 wherein said fluid isselected from the group of hydrocarbons consisting of n-butane, propane,isopentane and a mixture of the foregoing.
 11. A method of treating in ahuman or animal diabetes or a diabetes related condition capable oftreatment by oral or nasal inhalation, which comprises, administering aformulation according to claim 4 or to claim 1 to said human or animalby oral or nasal inhalation.
 12. A formulation according to claim 4 orclaim 1 in an aerosol canister equipped with a metered dose valve.
 13. Amethod of preparing a liquid medicinal aerosol suspension formulationaccording to claimed 4 or to claim 1, which comprises: (a) combining (i)said insulin combination in an amount sufficient to provide a pluralityof therapeutically effective doses, and (ii) said fluid carrier in anamount sufficient to propel said plurality of said therapeuticallyeffective doses from an aerosol canister; and (b) dispersing components(i) and (ii).
 14. The method as definedin claim 13 where if themedicinal aerosol formulation further comprises combining in step (a)(iii) a stabilizer in an effective stabilizing amount, and in step (b)dispersing components (i) and (ii) with said (iii) stabilizer.
 15. Themethod as defined in claim 14 which further comprises combining in step(a) a cosolvent, and in step (b) dispersing components (i), (ii) and(iii) with said cosolvent.
 16. A method as defined in claim 15 whereinsaid cosolvent is ethanol.
 17. A liquid medicinal aerosol suspensionformulation which consists essentially of: (a) a therapeuticallyeffective amount of an insulin computation which is a selected insulinor insulin analog combined with a β-cell hypoglycemic medicament whichis selected from the group consisting of an amylin and an amylin analogin combination with another diabetic medicament selected from the groupconsisting of glucagon, acetohexamide, chlorpropamide, tolazemide,tolbutamide, glipizide, glyburide, activin, somatostatin and a mixtureof any of the foregoing diabetic medicaments; and (b) a fluid propellantcarrier.
 18. The formulation as defined in claim 17 or claim 1 whereinsaid insulin combination is combined with glucagon.
 19. A liquidmedicinal aerosol suspension formulation which consists essentially of:(a) a therapeutically effective amount of an insulin combination whichis a selected insulin or insulin analog combined with at least one otherβ-cell hypoglycemic medicament; (b) a fluid propellant carrier; and (c)a water addition stabilizer added in an amount which is in addition tonascent formulation water.
 20. A metered dose inhaler containing aliquid medicinal aerosol suspension formulation, the formulationcomprising: (a) a therapeutically effective amount of an insulincombination which is an insulin analog combined with at least one otherβ-cell hypoglycemic medicament combined with a diabetic medicamentselected from the group consisting of glucagon, acetohexamide,chlorpropamide, tolazemide, tolbutamide, glipizide, glyburide,glucophage, phentolamine and a mixture of the foregoing diabeticmedicaments; (b) a fluid propellant carrier; and (c) a water additionstabilizer which is added in an amount which (1) is in excess of nascentformulation water and (2) stabilizes the formulation to preventsettling, creaming or flocculation for a time sufficient to allowreproducible dosing of the insulin combination after agitation of theformulation.
 21. The metered dose inhaler as defined in claim 20 whereinsaid diabetic medicament is glucagon.
 22. The metered dose inhaler asdefined in claim 20 wherein said hypoglycemic medicament is combinedwith a mixture of diabetic medicaments.
 23. The metered dose inhaler asdefined in claim 20 wherein said insulin combination comprises insulinanalog and a mixture of amylin and glucagon.
 24. The metered doseinhaler as defined in claim 20 wherein said formulation further includesa cosolvent.
 25. The metered dose inhaler as defined in claim 24 whereinsaid cosolvent is ethanol.
 26. A metered dose inhaler containing aliquid medicinal aerosol suspension formulation, the formulationconsisting essentially of: (a) an insulin combination in particulateform in a therapeutically effective amount; (b) a fluid propellantcarrier; and (c) a water addition stabilizer which is added in an amountwhich (1) is in excess of nascent formulation water and (2) stabilizesthe formulation to prevent settling, creaming or flocculation for a timesufficient to allow reproducible dosing of the insulin combination afteragitation of the formulation.
 27. The metered dose inhaler as defined inclaim 26 wherein said stabilizer is added in an amount in said excess ofabout 10 parts by weight to about 5000 parts by weight based on onemillion parts by total weight of the medicinal aerosol formulation. 28.The metered dose inhaler as defined in claim 26 wherein said insulincombination is (a) a selected insulin or a selected insulin analog; and(b) a β-cell amylin hypoglycemic or amylin analog.
 29. The metered doseinhaler as defined in claim 28 wherein said insulin is selected from thegroup consisting of natural, synthetic, recombinant insulin and amixture of the foregoing insulins.
 30. The metered dose inhaler asdefined in claim 28 wherein said selected insulin is an insulin selectedfrom lispro insulin, humalog insulin, hepatoselective insulin, andmonomeric insulin and a mixture of the foregoing.
 31. The metered doseinhaler as defined in claim 28 or claim 20 wherein said carrier is apropellant selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoroethane or a mixturethereof.
 32. The metered dose inhaler as defined in claim 28 or claim 20wherein said carrier is a hydrocarbon selected from n-butane, propane,isopentane and a mixture of any of the foregoing hydrocarbons.